Microglia play a central role in the control of brain inflammation. The phenotype of activated microglia varies depending on the pathology, from releasing toxins that harm adjacent cells, to decreasing the production of toxins and producing mediators that protect and repair adjacent cells. GPCRs expressed by microglia represent promising therapeutic targets to control the phenotype and function of these immune cells, ideally by favoring their healing responses and reducing their damaging potential. Our preliminary data suggest that microglia cell migration is modulated by a new adhesion GPCR, GPR125, that we found is activated by cannabinoid-like compounds. To study the pathophysiological role of these receptors, we developed JWH-451, an agonist that selectively activates GPR125 and found that it modulates the migration of both BV-2 cells and mouse microglia in primary culture. Here we propose to test the following hypothesis: Microglia function is regulated by cannabinoid-like compounds acting through GPR125, an adhesion GPCR. Selective agonists at GPR125 represent new pharmacological tools to study the involvement of microglia in controlling malignant astrocytoma pathogenesis. The following three aims will test this hypothesis: AIM 1: Identify the chemical determinants required for JWH-451 efficacy and selectivity at GPR125. AIM 2: How do GPR125 agonists regulate microglia cell function in vitro? AIM 3: How do GPR125 agonists regulate microglia cell function in vivo? The completion of this grant will increase our understanding of the molecular mechanism and cellular functions regulated by GPR125 in microglia. It will also provide new compounds that activate (and possibly antagonize) this receptor; pharmacological tools that have promising scientific and therapeutic value. PUBLIC HEALTH RELEVANCE: The goal of this RO1 is to characterize the molecular mechanisms and microglial cell functions regulated by GPR125, an adhesion GPCR expressed by microglia and involved in the control of brain inflammation. We will also test the therapeutic potential of GPR125 agonists in a mouse model of malignant astrocytomas.